The purpose of this B/START proposal is to investigate the consequences of repeated kappa opioid receptor (KOR) activation on brain stimulation reward. Both stress and drugs of abuse such as cocaine increase activity of the neuropeptide dynorphin (Hurd et al., 1992; Spangler et al., 1993; McLaughlin et al., 2003), the endogenous ligand for the KOR (Chavkin et al., 1982). Furthermore, stress and prior drug experience have been shown to enhance the rewarding effects of drugs of abuse, which-in humans-could facilitate the development of addiction (Koob and Le Moal, 1997; Lu et al., 2003). KOR agonists are dysphoric and attenuate locomotor stimulant and rewarding properties of cocaine when given acutely (Gray et al., 1999; McLaughlin et al., 2006). However, repeated activation of KOR's might lead to compensatory neural changes over time such that termination of the KOR activation could enhance the rewarding actions of cocaine. We hypothesize that repeated activation of KORs-as might occur during periods of stress or drug "binges"-will be dysphoric whereas a consequence of prior activation of KORs-as might occur after periods of stress or drug "binges"-will be an increase in the rewarding effects of cocaine. In prelimary studies we demonstrate that an acute injection of the highly potent and selective KOR agonist, Salvinorin A (SalvA) reduced cocaine- induced locomotor activity. In contrast, 24 hr after a 6-d regimen of repeated treatment with SalvA, cocaine- induced locomotor activity was increased. To determine the consequences of repeated KOR activation on reward, we will use intracranial self-stimulation (ICSS) to measure brain stimulation reward during a 6 day regimen of SalvA administration and measure the consequence of repeated SalvA administration on cocaine- enhanced brain stimulation reward 24 hr after the last SalvA injection. Additionally, in a control experiment, we will test whether the effects of repeated SalvA are KOR-specific by pre-treating rats with the KOR antagonist, norBNI. Our hypothesis predicts that brain stimulation reward will be decreased (reflected in an increase in ICSS thresholds) throughout the regimen of repeated KOR activation, whereas cocaine-enhanced brain stimulation reward will be increased (reflected in a decrease in ICSS thresholds) after the regimen of repeated KOR activation. Data from these studies will guide the formulation of future grant applications in which we will propose to elucidate the neurobiological mechanisms that underlie the effects of repeated KOR activation on brain stimulation reward.